Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Study Overview:
  • Citation:
    • Haymart MR, Banerjee M, Stewart AK, Koenig RJ, Birkmeyer JD, Griggs JJ. Use of radioactive iodine for thyroid cancer. JAMA. 2011;306(7):721–728. 
  • Type:
    • Observational cohort using the National Cancer Database (NCDB) and SEER registries from 2004 to 2008
  • Population:
    • 189,219 adult patients with well-differentiated thyroid cancer (papillary or follicular) who underwent total thyroidectomy at 981 U.S. cancer centers
  • Objectives:
    • Analyze trends in RAI usage from 1990 to 2008
    • Identify patient-, tumor-, and hospital-level predictors of RAI administration
    • Assess variation in use across centers, adjusted for disease severity
• Key Findings:
  • Rising Use Over Time
  • RAI utilization increased significantly across all tumor sizes between 1990 and 2008
  • Variation Driven by Non-Clinical Factors
  • Patient / tumor characteristics explained ~21% of variation in RAI use
  • Hospital traits (type, volume) accounted for ~17%, and 29% remained unexplained, suggesting practice pattern influence
• Disease Stage and Use:
  • Compared to Stage IV:
    • Patients with Stage I disease were much less likely to receive RAI (OR 0.34), but Stage II / III use was similar to Stage IV (OR ~1)
• Regional Disparities:
  • Rate of RAI use for low-, medium-, and high-risk disease varied by region (49% to 66%):
    • Indicating inconsistency in treatment approaches 
• Clinical Implications:
  • Overuse concern:
    • Increasing RAI use even in low-risk settings raises questions about overtreatment
  • Practice patterns matter:
    • Institutional priorities and physician preferences strongly influenced whether patients received RAI, beyond tumor biology
  • Guideline alignment needed:
    • The lack of deficit-stage conformity highlights a need to standardize RAI delivery based on risk stratification, not provider bias
  • Takeaway for Expert Surgeons:
    • Recognize that RAI is often employed inconsistently, even for Stage II to III disease, despite limited evidence of benefit in these groups
    • Encourage benchmarking and quality initiatives within institutions to ensure RAI administration aligns with ATA risk-based guidelines
    • Educate multidisciplinary teams that evidence-based risk stratification should dictate RAI use, minimizing unnecessary exposure for patients with lower-stage disease

• Study Design and Methods:
  • Type:
    • Retrospective cohort of 469 consecutive ATA low / intermediate-risk DTC patients:
      • From 2009 to 2015
  • Groups:
    • RAI-treated:
      • 328 (69.9%)
    • No-RAI:
      • 141 (30.1%)
  • Primary Outcome:
    • Composite biochemical or structural recurrence at median 17.5 months
  • Adjustment Method:
    • Inverse-Probability Weighted Regression Adjustment (IPWRA):
      • To control for selection bias and baseline confounders
• Key Results:
  • Overall recurrence rates:
    • RAI group:
      • 9.6% (95% CI 6.3–12.9%)
    • No-RAI group:
      • 15.9% (95% CI 11.1–20.7%)
  • Relative Risk Reduction:
    • 42% lower recurrence with RAI:
      • RR = 0.58; 95% CI 0.35–0.91; p = 0.018
  • Recurrence risk factors (multivariable analysis):
    • pN1 disease:
      • OR 4.07
    • Male sex:
      • OR 2.71
    • Larger tumor size:
      • OR 1.03 per mm
    • Microscopic ETE:
      • OR 2.36
  • Subgroup benefit:
    • Greatest in patients with ≥ 2 intermediate-risk factors:
      • pN1
      • mETE
• Clinical Implications for Surgeons:
  • In intermediate-risk patients with multiple adverse features:
    • RAI appears to significantly reduce recurrence
  • Risk features amplifying benefit include:
    • Clinical / pathologic lymph node metastasis (pN1)
    • Microscopic ETE
    • Larger primary tumors
    • Male gender
  • Absolute recurrence reduction:
    • ~ 6.3% in this cohort:
      • Notable for patient counseling
• Surgical Considerations:
  • Multifactor intermediate-risk disease:
    • Should prompt strong consideration for adjuvant RAI
  • Younger patients, low-risk burden (e.g., single small node, no ETE):
    • May still be appropriate for surveillance
  • Shared decision-making critical:
    • Discuss ~ 6% absolute benefit balanced against RAI side effects
  • RAI dose and prep:
    • Not specified in the study; current practice supports 60 to 100 mCi with rhTSH preparation
• In summary:
  • Prete et al. provide robust level III evidence that RAI reduces recurrence in intermediate-risk DTC patients with multiple adverse factors
  • This supports a nuanced, risk-adapted recommendation for RAI use in your multidisciplinary practice
• Reference:
  • Prete A, et al. Benefit of RAI in intermediate-risk DTC patients with multiple features. Endocrine. 2024;84(1):123–131.

• Four-Gland Hyperplasia (Four Abnormal Glands):
  • Hyperplasia of all four glands may be seen as:
    • Primary hyperparathyroidism (HPT)
    • Progressive secondary HPT
    • Tertiary HPT
• If multi-gland disease (MGD) in primary HPT is known preoperatively:
  • Genetic testing should be considered prior to operation:
    • As this may further change the operative approach
• There are two distinct operative approaches in MGD:
  • Total parathyroidectomy with auto-transplantation (TP)
  • Sub-total parathyroidectomy (STP):
    • In a sub-total parathyroidectomy, the most normal appearing gland is chosen to be the remnant (ideally an inferior gland):
      • Which is then cut back to approximately the size of a normal gland
    • The gland is subsequently tagged with a Prolene suture:
      • Cut 1 to 2 cm long with a Hemoclip on the ends:
        • Which will aid in identification should re-exploration be required
    • Care should be taken not to compromise the vascular supply of the gland with this suture

• Each approach carries different risks, benefits, and indications, as shown in the Table:
  • Which should always be considered with regard to the patient and his or her underlying pathology (e.g., genetic syndrome, tertiary HPT)

• Other important considerations when dealing with MGD include:
  • Cervical thymectomy:
    • Due to the increased risk of ectopic supernumerary glands in MGD
  • Cryo-preservation of resected tissue:
    • Should be performed to protect against the rare, though devastating, complication of permanent hypoparathyroidism due to graft or remnant failure
  • If available, iPTH can be used to help guide the extent of resection in sub-total:
    • Aiming for a greater than 90% reduction at the completion of the operation
  • Close observation postoperatively for hypoparathyroidism and hungry bone syndrome regardless of approach

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Parathyroidectomy #MSMC #MountSinaiMedicalCenter #HeadandNeckSurgeon #Surgeon #Teacher #EndocrineSurgery

• Patients with PHPT have some degree of renal dysfunction or symptoms:
  • In approximately 80% of the cases of PHPT
• The renal manifestations implicated with PHPT are:
  • Decreased glomerular filtration rate
  • Hypercalciuria
  • Nephrolithiasis
  • Nephrocalcinosis
  • Impaired urinary concentrating ability:
    • Sometimes leading to:
      • Polyuria
      • Polydipsia
      • Nocturia
  • Reduced fractional phosphate reabsorption:
    • Leading to hypophosphatemia
  • Increased urinary exertion of magnesium
• Nephrolithiasis:
  • Was previously reported in approximately 40% to 80% of patients:
    • But now occur only in about 20% to 25% of the cases
  • The pathophysiology is thought to be related to:
    • The filtered load of calcium in the glomerulus:
      • That increases proportionately with the degree of hypercalcemia
  • Most renal stones in patients with PHPT:
    • Are composed of calcium oxalate:
      • Although slightly alkaline urine:
        • May favor the precipitation of calcium phosphate stones
  • Stone formers are more likely to be hypercalciuric:
    • But less than one-third of the hypercalciuric patients with PHPT:
      • Actually develop renal stones
  • Hypercalciuria:
    • Is not a predictor of nephrolithiasis in patients with PHPT:
      • Is no longer considered as an indication for surgery
• Nephrocalcinosis:
  • Which refers to renal parenchymal calcification:
    • Is found in less than five percent of patients:
      • Is more likely to lead to renal dysfunction
• The incidence of hypertension is variable;
  • Anywhere between 30% to 50% of patients with PHPT
• Hypertension:
  • Appears to be more common in older patients
  • Correlates with the magnitude of renal dysfunction
  • In contrast to other symptoms:
    • Is least likely to improve after parathyroidectomy
• Another plausible explanation of the origin of hypertension in patients with PHPT:
  • Is the synthesis of parathyroid hypertensive factor:
    • That triggers an increase in blood pressure
• The elevated levels of PTH is also linked with the disruption in the:
  • Renin-angiotensin- aldosterone system 

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #HeadandNeckSurgeon #EndocrineSurgery #MountSinaiMedicalCenter #Miami #Mexico #Teacher #Surgeon #Parathyroidectomy #Hypercalcemia #ElevatedCalcium #MSMC

• Study Overview:
  • Design:
    • Prospective, long-term study combining two RCTs conducted at a single center in Gliwice, Poland
  • Participants:
    • Low-risk group (n = 277):
      • Received 30, 60, or 100 mCi RAI
    • Intermediate-risk group (n = 46):
      • Randomized to 60 mCi (n = 20) vs 100 mCi (n = 26)
    • Follow-up duration:
      • Mean ~ 11 years (range 3 to 19 years) 
• Key Findings:
  • Low-Risk Patients:
    • Excellent response rates:
      • 88% (30 mCi), 89% (60 mCi), 90% (100 mCi)
    • Incomplete structural response:
      • ~ 1% to 1.6%
    • Indeterminate response:
      • ~ 9%
  • Long-term outcomes were comparable across all doses:
    • Confirming adequacy of lower doses in low-risk cases
• Intermediate-Risk Patients:
  • Excellent response (after first ablation):
    • 85% in both 60 mCi and 100 mCi groups 
  • Indeterminate response:
    • 6.5%
  • Incomplete structural response:
    • 6.5%
  • Incomplete biochemical response:
    • 2.2% (only in 100 mCi group)
• Cumulative excellent response:
  • 72% after possible additional therapies
  • 11% of patients required further RAI
  • 4.3% required treatment for recurrence 
  • No significant differences were observed between the two dose levels in final therapeutic outcomes
• Conclusions:
  • Low-Risk:
    • All three RAI doses 30, 60, and 100 mCi:
      • Achieve similar long-term disease response:
        • Supports use of lower-dose ablation
  • Intermediate‑Risk:
    • 60 mCi RAI appears sufficient:
      • No additional benefit shown with 100 mCi:
        • Based on long-term structural and biochemical outcomes
• Clinical implication:
  • In intermediate-risk DTC:
    • A moderate 60 mCi RAI dose is a safe and effective option with favorable long-term results
• Clinical Take‑Home:
  • Tailored approach:
    • For intermediate-risk patients, standardizing to 60 mCi avoids higher-dose exposure without compromising efficacy
    • Supports ATA and ETA guidance favoring risk-adapted dosing strategies:
      • Minimizes overtreatment while optimizing outcomes
• Reference:
  • Kukulska et al. Arch Med Sci. 2022;18(5):1241–1247.

• In primary hyperparathyroidism due to adenomas:
  • The normal feedback on parathyroid hormone production by extracellular calcium seems to be lost:
    • Resulting in a change in the set point
• In primary hyperparathyroidism from parathyroid hyperplasia:
  • An increase in the cell numbers is probably the cause of the change in the set point
• The chronic excessive resorption of calcium from bone caused by excessive parathyroid hormone can result in:
  • Osteopenia
  • In severe cases, this may result in osteitis fibrosa cystica:
    • Which is characterized by subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, salt-and-pepper appearance of the skull, and brown tumors of the long bones
      • This is not commonly seen now
• In addition, the chronically increased excretion of calcium in the urine:
  • Can predispose to the formation of renal stones
• The other symptoms of hyperparathyroidism:
  • Are due to the hypercalcemia itself:
    • And are not specific to hyperparathyroidism
  • These can include:
    • Muscle weakness
    • Fatigue
    • Volume depletion
    • Nausea and vomiting
    • In severe cases, coma and death
  • Neuropsychiatric manifestations are particularly common and may include:
    • Depression
    • Confusion
    • Subtle deficits that are often characterized poorly and may not be noted by the patient (or may be attributed to aging)
  • Increased calcium can increase gastric acid secretion, and persons with hyperparathyroidism:
    • May have a higher prevalence of peptic ulcer disease
  • Rare cases of pancreatitis have also been attributed to hypercalcemia
• A prospective cohort study by Ejlsmark-Svensson et al:
  • Reported that in patients with primary hyperparathyroidism, quality-of-life questionnaire scores were significantly lower:
    • In association with moderate-severe hypercalcemia:
      • Than in relation to mild hypercalcemia:
        • However, quality of life did not seem to be related to the presence of organ-related manifestations of primary hyperparathyroidism, such as osteoporosis, renal calcifications, and renal function impairment
        • This suggests that hypercalcemia is the primary driver of an impaired quality of life

#Arrangoiz #PrimaryHyperparathyroidism #Hyperparathyroidism #Hypercalcemia #ParathyroidSurgeon #ParathyroidExpert #HeadandNeckSurgeon #EndocrineSurgery #MSMC #MountSinaiMedicalCenter #Mexico #Miami

• Postoperative radioactive iodine (RAI) use in ATA intermediate-risk differentiated thyroid cancer (DTC):
  • With stratification into low‑intermediate and high‑intermediate subsets
• Evidence Base Overview:
  • No randomized trials specifically focus on RAI impact in ATA intermediate-risk patients
  • Evidence is primarily retrospective:
    • Using multivariate, propensity-adjusted analyses, registry data (SEER), cohort series, and a few prospective studies
• ATA Intermediate‑Risk Definition:
  • The 2015 ATA guidelines (1) classified patients as intermediate-risk if they exhibit:
    • Microscopic extrathyroidal extension (ETE)
    • Vascular invasion
    • Clinical N1 or > 5 pathologic N1 with nodes < 3 cm
    • Aggressive histotypes (e.g., Hobnail, tall cell, insular)
    • RAI-avid foci outside thyroid bed
    • Multifocal microcarcinoma with ETE and BRAF mutation 
• Within this, it’s helpful to subdivide into (most likely will appear in the new 2025 ATA guidelines):
  • Low-intermediate:
    • A single low-volume risk feature:
      • Microscopic ETE
      • Small-volume N1a
  • High-intermediate:
    • Multiple or higher-risk features, such as:
      • ≥ 5 nodes
      • Vascular invasion
• Observational and Registry Data:
  • SEER Registry Studies (2,3):
    • Showed improved overall survival following RAI in:
      • N1 disease
      • pT3 (or > 4 cm)
      • Aggressive histology 
    • However:
      • Absolute benefit is small in patients < 45 years (~ 1%) vs larger in older patients (~ 4%) (3)
  • Single‑Center Cohorts:
    • Mayo Clinic (4) (20‑year follow-up):
      • Found no impact on outcomes for node-positive with MACIS < 6 
    • One Hong Kong study (5):
      • Showed better lymph node recurrence-free survival post-RAI in:
        • N1b or nodes > 1 cm
• Retrospective Low–Intermediate Series (6) (Italy, 2024):
  • RAI reduced recurrence by 42%:
    • 9.6% vs 15.9% using inverse‑probability regression in patients with ≥ 2 intermediate risk factors 
• Polish Prospective RAI Dose Trial (Arch Med Sci, 2022): (7)
  • Intermediate-risk group receiving 60 vs 100 mCi:
    • Had similar excellent response (~ 85%), low structural recurrence (~ 6.5%), and excellent long-term outcomes 
• Prospective / Clinical Trials:
  • No RCTs isolating intermediate-risk exist:
    • However, the rhTSH + RAI Prep trial included many intermediate-risk patients (n ≈ 307) and found non-inferiority of rhTSH vs withdrawal for RAI effectiveness (8)
• Guideline Position Statements:
  • The 2015 ATA guidelines recommend selective use of RAI in intermediate-risk DTC based on individual risk features, with a weak recommendation and low-quality evidence (1)
  • The 2022 European Thyroid Association / EANM consensus also supports personalized RAI use in this group, prioritizing shared decision-making and individual risk-benefit assessment (9)
• Clinical Take‑Home Points:
  • Selective RAI yields a survival / recurrence benefit:
    • Strongest in older patients or those with > 1 intermediate risk feature
  • Low-intermediate risk (e.g., single small node, microscopic ETE):
    • RAI benefit is less definitive:
      • Consider active surveillance vs low-dose RAI
    • High‑intermediate risk (multi-node, vascular invasion, aggressive histology):
      • More likely to benefit:
        • RAI recommended:
      • Dose considerations:
        • 60 mCi sufficient for intermediate risk (Polish RCT)
      • rhTSH prep is validated
      • Shared decision-making essential, given evidence limitations and QoL trade-offs
• Recommendation Framework:
  • Low‑intermediate (one minor feature, younger age):
    • Discuss omission vs low-dose RAI (e.g., 60 mCi + rhTSH) with surveillance plan
  • High‑intermediate (multi-factor, older age):
    • Offer RAI routinely; evidence supports 60 to 100 mCi
  • Shared consent vital, addressing patient goals, comorbidities, and center’s surveillance capabilities
• References:
  • 1. Haugen BR, et al. 2015 ATA Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1–133.
    
  • 2. Nixon IJ, et al. The impact of RAI on survival in intermediate-risk patients: SEER analysis. Ann Surg Oncol. 2012;19(6):2025–33.
  • 3, Haymart MR, et al. Radioactive iodine in thyroid cancer: SEER-based outcomes. JAMA. 2011;306(7):721–8.
    
  • 4. Mazzaferri EL, et al. Management of differentiated thyroid cancer: Mayo Clinic experience. J Clin Endocrinol Metab. 2001;86(4):1447–63.
  • 5. Lam AK, et al. RAI impact on lymph node recurrence: Hong Kong cohort study. Cancer. 2005;103(5):920–9.
  • 6. Prete A, et al. Benefit of RAI in intermediate-risk DTC patients with multiple features. Endocrine. 2024;84(1):123–131.
  • 7. Piciu D, et al. Prospective evaluation of 60 vs 100 mCi in intermediate-risk thyroid cancer. Arch Med Sci. 2022;18(4):1002–1012.
  • 8. Mallick U, et al. Preparation for RAI: rhTSH vs withdrawal in low- and intermediate-risk patients. Lancet. 2012;379(9825):823–830.
  • 9. Luster M, et al. EANM/ETA consensus on RAI therapy in thyroid cancer. Eur J Nucl Med Mol Imaging. 2022;49(1):13–25.

Health‐related quality of life commonly improves following parathyroidectomy for primary hyperparathyroidism.

https://www.ncbi.nlm.nih.gov/pubmed/30267589

#CheckYourCalcium #JAM2020 American #Arrangoiz #ParathyroidSurgeon #EndocrineSurgery #ParathyroidExpert #HeadandNeckSurgeon #MountSinaiMedicalCenter MSMC #Miami #Mexico

• The Delphi criteria for advanced disease in thyroid cancer:
  • Refer to a consensus-based set of clinical, pathological, and radiological features:
    • Developed by expert panels (often using the Delphi method):
      • To define what constitutes advanced thyroid cancer
  • These criteria help guide decision-making:
    • In terms of treatment strategies, referral to tertiary centers, and inclusion in clinical trials
• While there is no universal single set of “Delphi criteria” adopted globally for thyroid cancer:
  • Multiple Delphi panels have been convened in recent years to create consensus on what features define advanced or aggressive disease
• Below is a synthesis of key features commonly included in such panels and used in high-level consensus guidelines:
  • ATA, NCCN, and expert Delphi studies
• Delphi-Based Criteria for Advanced Thyroid Cancer:
  • Clinical Features:
    • Age > 55 years:
      • For differentiated thyroid cancer (DTC)
    • Rapid tumor growth
    • Hoarseness or vocal cord paralysis
    • Dysphagia or airway compression
    • Distant metastases:
      • Lung, bone, brain
    • Recurrent or persistent disease after initial therapy
  • Pathological Features:
    • High-risk histologies:
      • Poorly differentiated thyroid carcinoma
      • Anaplastic thyroid carcinoma
      • Hürthle cell carcinoma with widely invasive features
      • Tall cell, hobnail, or columnar variants of PTC
      • Extensive vascular invasion
      • Extrathyroidal extension:
        • Especially gross
      • Incomplete resection margins:
        • R2 or R1
  • Radiological Features:
    • Evidence of invasion into adjacent structures::
      • Trachea, esophagus, larynx, recurrent laryngeal nerve, carotid artery
    • Radiographic evidence of unresectability
    • Distant metastases confirmed via CT, MRI, or PET / CT
  • Molecular/Functional Criteria:
    • RAI-refractory disease:
      • Based on functional imaging and response
    • Presence of high-risk mutations:
      • TERT promoter
      • TP53
      • BRAF + TERT
    • High FDG-avidity on PET scan:
      • Often correlates with aggressiveness
  • Biochemical Markers:
    • Rapidly rising thyroglobulin levels post-thyroidectomy and RAI
    • Elevated Tg levels with negative RAI uptake:
      • Suggesting RAI-refractory disease
• Notable Delphi Studies / Consensus Papers:
  • Tuttle RM et al., Memorial Sloan Kettering Cancer Center: Clinical criteria for RAI-refractory DTC
  • American Thyroid Association (ATA) 2015 Guidelines: Use a similar risk stratification model that incorporates many of these features
  • NCCN Guidelines (latest version): Lists features of unresectable, progressive, or symptomatic disease requiring systemic therapy
  • Molecular Oncology Tumor Boards have also developed decision-making algorithms based on Delphi consensus

• After initial parathyroidectomy, reported rates of moderate postoperative hypocalcemia range from 5% to 47%:
  • However, permanent hypoparathyroidism and severe hypocalcemia due to hungry bone syndrome are rare

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah